Kidney cell function requires the maintenance of polarized plasma membrane domains with distinct protein and lipid compositions, and defects in proper targeting of proteins results in disease. Despite the critical role of cell polarity in maintaining kidney function, we know little about the mechanisms that selectively guide proteins to the apical and basolateral cell surfaces. Our long term goal is to understand how proteins are segregated and targeted to the apical surface of kidney cells with the objective of manipulating protein sorting to treat disease. Apical sorting signals are diverse and multiple biosynthetic routes exist to the apical plasma membrane. Here we propose a unifying model for apical protein sorting in which cargo clustering within sorting compartments provides the avidity necessary to recruit membrane and cytoplasmic proteins required for surface delivery. We will test this model using a protein with an essential role in kidney function that is targeted to the apical surface in a glycan dependent manner. Our proposed studies utilize cutting edge biophysical, biochemical, and proteomic approaches and take full advantage of the unique facilities and broad expertise in renal epithelial cell biology at the University of Pittsburgh. Ths work will significantly enhance our understanding of how apical sorting and polarity are maintained in the kidney and illuminate new strategies to manipulate protein traffic for therapeutic advantage.